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Event: 402

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Cognitive Function, Decreased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Cognitive Function, Decreased
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
learning or memory decreased
cognition decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TPO Inhibition and Altered Neurodevelopment AdverseOutcome Kevin Crofton (send email) Open for citation & comment WPHA/WNT Endorsed
NIS and Neurodevelopment AdverseOutcome Kevin Crofton (send email) Not under active development
NIS and Cognitive Dysfunction AdverseOutcome Mary Gilbert (send email) Under Development: Contributions and Comments Welcome
Transthyretin interference AdverseOutcome Kristie Sullivan (send email) Under Development: Contributions and Comments Welcome Under Development
TR Antagonism and DNT AdverseOutcome Kevin Crofton (send email) Under development: Not open for comment. Do not cite Under Development
Organo-Phosphate Chemicals leading to impaired cognitive function AdverseOutcome SAROJ AMAR (send email) Under development: Not open for comment. Do not cite
TR antagonism leading to decreased cognition AdverseOutcome Eliska Kuchovska (send email) Under development: Not open for comment. Do not cite
Binding to laminin and DNT AdverseOutcome Eliska Kuchovska (send email) Under development: Not open for comment. Do not cite
Cholesterol metabolism and DNT AdverseOutcome Eliska Kuchovska (send email) Under Development: Contributions and Comments Welcome
Increased ROS and DNT AdverseOutcome Eliska Kuchovska (send email) Under development: Not open for comment. Do not cite
Voltage-gated sodium channels and DNT AdverseOutcome Eliska Kuchovska (send email) Under development: Not open for comment. Do not cite
AhR activation in the liver leading to Adverse Neurodevelopmental Outcomes in Mammals AdverseOutcome Prakash Patel (send email) Under development: Not open for comment. Do not cite
AhR activation in the thyroid leading to Adverse Neurodevelopmental Outcomes in Mammals AdverseOutcome Prakash Patel (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During brain development High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Male High
Female High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems constituting functionally integrated neural networks (D’Hooge and DeDeyn, 2001). Among the many brain areas engaged in the acquisition of, or retrieval of, a learned event, the hippocampal-based memory systems have received the most study. The main learning areas and pathways are similar in rodents and primates, including man (Eichenbaum, 2000; Stanton and Spear, 1990; Squire, 2004).

In humans, the hippocampus is involved in recollection of an event’s rich spatial-temporal contexts and distinguished from simple semantic memory which is memory of a list of facts (Burgess et al., 2000). Hemispheric specialization has occurred in humans, with the left hippocampus specializing in verbal and narrative memories (i.e., context-dependent episodic or autobiographical memory) and the right hippocampus, more prominently engaged in visuo-spatial memory (i.e., memory for locations within an environment). The hippocampus is particularly critical for the formation of episodic memory, and autobiographical memory tasks have been developed to specifically probe these functions (Eichenbaun, 2000; Willoughby et al., 2014). In rodents, there is obviously no verbal component in hippocampal memory, but reliance on the hippocampus for spatial, temporal and contextual memory function has been well documented. Spatial memory deficits and fear-based context learning paradigms engage the hippocampus, amygdala, and prefrontal cortex (Eichenbaum, 2000; Shors et al., 2001; Samuels et al., 2011; Vorhees and Williams, 2014; D’Hooge and DeDeyn, 2001; Lynch, 2004; O’Keefe and Nadal, 1978). These tasks are impaired in animals with hippocampal dysfunction (O’Keefe and Nadal, 1978; Morris and Frey, 1987; Gilbert et al., 2016).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

In rodents, a variety of tests of learning and memory have been used to probe the integrity of hippocampal function. These include tests of spatial learning like the radial arm maze (RAM), the Barnes maze, and most commonly, the Morris water maze (MWM). Test of novelty such as novel object recognition, and fear based context learning are also sensitive to hippocampal disruption. Finally, trace fear conditioning which incorporates a temporal component upon traditional amygdala-based fear learning engages the hippocampus. A brief description of these tasks follows.

1) RAM, Barnes, MWM are examples of spatial tasks in which animals are required to learn: the location of a food reward (RAM); an escape hole to enter a preferred dark tunnel from a brightly lit open field area (Barnes maze); or a hidden platform submerged below the surface of the water in a large tank of water (MWM) (Vorhees and Williams, 2014).

2) Novel Object recognition. This is a simpler task that can be used to probe recognition memory. Two objects are presented to animal in an open field on trial 1, and these are explored. On trial 2, one object is replaced with a novel object and time spent interacting with the novel object is taken evidence of memory retention (i.e., I have seen one of these objects before, but not this one. Cohen and Stackman, 2015).

3) Contextual Fear conditioning is a hippocampal based learning task in which animals are placed in a novel environment and allowed to explore for several minutes before delivery of an aversive stimulus, typically a mild foot shock. Upon reintroduction to this same environment in the future (typically 24-48 hours after original training), animals will limit their exploration, the context of this chamber being associated with an aversive event. The degree of suppression of activity after training is taken as evidence of retention, i.e., memory (Curzon et al., 2009).

4) Trace fear conditioning. Standard fear conditioning paradigms require animals to make an association between a neutral conditioning stimulus (CS, a light or a tone) and an aversive stimulus (US, a footshock). The unconditioned response (CR) that is elicited upon delivery of the footshock US is freezing behavior. With repetition of CS/US delivery, the previously neutral stimulus comes to elicit the freezing response. This type of learning is dependent on the amygdala, a brain region associated with, but distinct from the hippocampus. Introducing a brief delay between presentation of the neutral CS and the aversive US, a trace period, requires the engagement of the amygdala and the hippocampus (Shors et al., 2004).

Most methods are well established in the published literature and many have been engaged to evaluate the effects of developmental thyroid disruption. The US EPA and OECD Developmental Neurotoxicity (DNT) Guidelines (OCSPP 870.6300 or OECD 426) both require testing of learning and memory (USEPA, 1998; OECD, 2007). These DNT Guidelines have been deemed valid to identify developmental neurotoxicity and adverse neurodevelopmental outcomes (Makris et al., 2009).

A variety of standardized learning and memory tests have been developed for human neuropsychological testing. These include episodic autobiographical memory, word pair recognition memory; object location recognition memory. Some components of these tests have been incorporated in general tests of adult intelligence (IQ) such as the WAIS and the Wechsler. Modifications have been made and norms developed for incorporating of tests of learning and memory in children. Examples of some of these tests include:

1) Rey Osterieth Complex Figure (RCFT) which probes a variety of functions including as visuospatial abilities, memory, attention, planning, and working memory (Shin et al., 2006).

2) Children’s Auditory Verbal Learning Test (CAVLT) is a free recall of presented word lists that yields measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak 1995; Talley, 1986). 

3) Continuous Visual Memory Test (CVMT) measures visual learning and memory. It is a free recall of presented pictures/objects rather than words but that yields similar measures of Immediate Memory Span, Level of Learning, Immediate Recall, Delayed Recall, Recognition Accuracy, and Total Intrusions. (Lezak, 1984; 1994).

4) Story Recall from Wechsler Memory Scale (WMS) Logical Memory Test Battery, a standardized neurospychological test designed to measure memory functions (Lezak, 1994; Talley, 1986).

5) Autobiographical memory (AM) is the recollection of specific personal events in a multifaceted higher order cognitive process. It includes episodic memory- remembering of past events specific in time and place, in contrast to semantic autobiographical memory is the recollection of personal facts, traits, and general knowledge. Episodic AM is associated with greater activation of the hippocampus and a later and more gradual developmental trajectory. Absence of episodic memory in early life (infantile amnesia) is thought to reflect immature hippocampal function (Herold et al., 2015; Fivush, 2015).

6) Staged Autobiographical Memory Task. In this version of the AM test, children participate in a staged event involving a tour of the hospital, perform a series of tasks (counting footprints in the hall, identifying objects in wall display, buy lunch, watched a video). It is designed to contain unique event happenings, place, time, visual/sensory/perceptual details. Four to five months later, interviews are conducted using Children’s Autobiographical Interview and scored according to standardized scheme (Willoughby et al., 2014).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Basic forms of learning behavior such as habituation have been found in many taxa from worms to humans (Alexander, 1990). More complex cognitive processes such as executive function likely reside only in higher mammalian species such as non-human primates and humans.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

A prime example of impairments in cognitive function as the adverse outcome for regulatory action is developmental lead exposure and IQ function in children (Bellinger, 2012). In addition, testing for the impact of chemical expsoures on cognitive function, often including spatially-mediated behaviors, is an intergral part of both EPA and OECD developmental neurotoxicity guidelines (USEPA, 1998; OECD, 2007).


List of the literature that was cited for this KE description. More help

Alexander RD (1990) Epigenetic rules and Darwinian algorithms: The adaptive study of learning and development. Ethology and Sociobiology 11:241-303.

Bellinger DC (2012) A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Perspect 120:501-507.

Burgess N (2002) The hippocampus, space, and viewpoints in episodic memory. Q J Exp Psychol A 55:1057-1080.

Cohen, SJ and Stackman, RW. (2015). Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav. Brain Res. 285: 105-1176.

Curzon P, Rustay NR, Browman KE. Cued and Contextual Fear Conditioning for Rodents. In: Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2009

D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60-90.

Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41-50.

Fivush R. The development of autobiographical memory. Annu Rev Psychol. 2011. 62:559-82.

Gilbert ME, Sanchez-Huerta K, Wood C (2016) Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157:774-787.

Gilbert ME, Sui L (2006) Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain Res 1069:10-22.

Herold, C, Lässer, MM, Schmid, LA, Seidl, U, Kong, L, Fellhauer, I, Thomann, PA, Essig, M and Schröder, J. (2015). Neuropsychology, Autobiographical Memory, and Hippocampal Volume in “Younger” and “Older” Patients with Chronic Schizophrenia. Front. Psychiatry, 6: 53.

Lezak MD (1984) Neuropsychological assessment in behavioral toxicology--developing techniques and interpretative issues. Scand J Work Environ Health 10 Suppl 1:25-29.

Lezak MD (1994) Domains of behavior from a neuropsychological perspective: the whole story. Nebr Symp Motiv 41:23-55.

Lynch, M.A. (2004). Long-Term Potentiation and Memory. Physiological Reviews. 84:87-136.

Makris SL, Raffaele K, Allen S, Bowers WJ, Hass U, Alleva E, Calamandrei G, Sheets L, Amcoff P, Delrue N, Crofton KM. A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect. 2009 Jan;117(1):17-25.

Morris RG, Frey U. Hippocampal synaptic plasticity: role in spatial learning or the automaticrecording of attended experience? Philos Trans R Soc Lond B Biol Sci. 1997 Oct 29;352(1360):1489-503. Review

O’Keefe, J. and Nadel, L. (1978). The Hippocampus as a Cognitive Map. Oxford: Oxford University Press.

OECD. 2007. OECD guidelines for the testing of chemicals/ section 4: Health effects. Test no. 426: Developmental neurotoxicity study.  www.Oecd.Org/dataoecd/20/52/37622194.Pdf [accessed May 21, 2012].

Samuels BA, Hen R (2011) Neurogenesis and affective disorders. Eur J Neurosci 33:1152-1159.

Shin, MS, Park, SY, Park, SR, Oeol, SH and Kwon, JS. (2006). Clinical and empirical appliations fo the Rey-Osterrieth complex figure test. Nature Protocols, 1: 892-899.

Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372-376.Squire LR (2004) Memory systems of the brain: a brief history and current perspective. Neurobiol Learn Mem 82:171-177.

Stanton ME, Spear LP (1990) Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals. Neurotoxicol Teratol 12:261-267.

Talley, JL. (1986). Memory in learning disabled children: Digit span and eh Rey Auditory verbal learning test. Archives of Clinical Neuropsychology, Elseiver.

U.S.EPA. 1998. Health effects guidelines OPPTS 870.6300 developmental neurotoxicity study. EPA Document 712-C-98-239.Office of Prevention Pesticides and Toxic Substances.

Vorhees CV, Williams MT (2014) Assessing spatial learning and memory in rodents. ILAR J 55:310-332.

Willoughby KA, McAndrews MP, Rovet JF. Accuracy of episodic autobiographical memory in children with early thyroid hormone deficiency using a staged event. Dev Cogn Neurosci. 2014. 9:1-11.